Molecular and atomic analysis, such as mass spectrometry, has proven to be an effective analytical technique for identifying unknown compounds and for determining the precise mass of known compounds. Advantageously, compounds can be detected or analyzed in minute quantities allowing compounds to be identified at very low concentrations in chemically complex mixtures. Not surprisingly, mass spectrometry has found practical application in medicine, pharmacology, food sciences, semi-conductor manufacturing, environmental sciences, security, and many other fields.
A typical molecular analyzer includes an ion source that ionizes particles of interest. In a mass spectrometer, the ions are passed to an analyzer, where they are separated according to their mass (m)-to-charge (z) ratios (m/z). The separated ions are detected at a detector. A signal from the detector may be sent to a computing or similar device where the m/z ratios may be stored together with their relative abundance for presentation in the format of a m/z spectrum. Mass spectrometers are discussed generally in “Electrospray Ionization Mass Spectrometry, Fundamentals, Instrumentation & Applications” edited by Richard B. Cole (1997) ISBN 0-4711456-4-5 and documents referenced therein.
Electrospray ionization is a widely used ionization technique for mass spectrometry, due to its ability to generate large molecular ions with minimal fragmentation. Analyte sample is typically dissolved in a solvent and buffer mixture held at a pH to enhance formation of molecular adducts in solution. Commonly analyte liquid, including analyte sample dissolved in one or more solvents, is delivered through a small capillary tube positioned within a large volume plenum chamber. The plenum chamber houses the capillary tube and an exhaust drain for the liquid flow. Commonly, the mass spectrometer sampling orifice is positioned in the plenum chamber, in close proximity to the capillary tube.
Electrospray ions are generated by a high voltage applied to the capillary tube. An electric field is established between the capillary tube and a surface in close proximity to the sampling orifice of the mass spectrometer—usually the sampling orifice itself. The electric field is very strong at the tip of the capillary and, through the electrospray induces charge separation. As a result the liquid sample is nebulized and an ion plume is established.
For liquid flow rates above 1 uL/min, nebulization of the charged liquid is usually aided by a tube coaxial with the capillary tube and terminating close to the capillary tip, between which flows a high velocity nebulizing gas. Sometimes, an additional heat gas flow is added for desolvation of the liquid droplets at higher liquid flow rates. The resulting mixture of droplets, ions and nebulizing gas flow is sampled by a sampling orifice leading to the inlet of the analyzer.
While this approach provides a convenient way of coupling an electrospray ion source to the sampling orifice of a molecular analyzer/mass spectrometer, it has disadvantages resulting largely from the direct sampling of ions generated by the capillary tube by the sampling inlet of the analyzer, due to the proximate coupling of the capillary tube with the sampling orifice via an open volume plenum chamber.
Further, the optimum ESI signal/noise is dependent upon positioning of capillary tip, as well as the position of the capillary tip relative to the nebulizer tip both radially and axially, the nebulizer flow rate, and heat gas flow rate, which are all functions of sample flow rate, and the analyte itself. As a consequence, ions from the ion source are not efficiently sampled by the mass analyzer, causing reduced sensitivity of the mass spectrometer. Often, additional manual or automatic adjustment of the source position is required, decreasing ease of use an increasing cost and complexity.
Further, desolvation from the ESI source is typically incomplete at the analyzer inlet, since there is insufficient time for energy and heat transfer during time that the charged droplets pass from the tip of the ESI sprayer and into the entrance of the mass spectrometer. This tends to cause an increase in signal fluctuation, reducing the quality of the measurement, and a reduction in the number of analyte ions produced. Thus fewer analyte ions are sampled by the mass spectrometer.
Most ion sources use large volume plenum chambers, but transporting ions efficiently toward the analyzer within the plenum chamber is problematic. The mixing of the liquid and nebulizing gas with the background gas can diffuse the plume of ions outward, away from the sampling orifice, also reducing sensitivity.
As well, because the plenum volume may be largely characterized by stagnated ambient pressure in regions near the sampling orifice of a mass spectrometer, electric fields are often required to deliver these ions to the sampling orifice of the analyzer. The focusing fields are achieved by applying a high voltage (typically about one kV) to a conductive plate or cone at the entrance of the mass spectrometer. However, use of electric fields at atmospheric pressure is inefficient, due to the inability to focus ions at the necessarily high collision rates between background gas and ions. Furthermore, contamination falling on the conductive plate or cone can cause a change in its conductivity, thereby changing the electric field produced by the applied voltage. This reduces both the sensitivity and stability of the mass spectrometer.
Also, because the analyzer sampling inlet is positioned in the plenum chamber, in close proximity to the capillary tube, any contamination produced by the liquid analyte is sampled by the analyzer, producing further contamination of the analyzer. The capillary tube is disadvantageously positioned close to the entrance, resulting in undesirable occasional electric discharge, and further providing even more contamination to enter the mass spectrometer.
These disadvantages are even more problematic for multiple ion sources that operate simultaneously within the same volume. The use of multiple ion sources may increases the number of samples analyzed per unit time (sample throughput) and therefore the information content per unit time.
Other types of ion sources suffer from similar shortcomings. Specifically, atmospheric pressure chemical ionization (APCI) and atmospheric pressure matrix assisted laser desorption ionization (MALDI) also provide issues with contamination and day to day fluctuations in optimization, with simultaneously operating sources even more difficult to use and optimize.
Accordingly, there is a need for an improved ion source that decouples the ion source and analyzer sampling orifice.